Process for the preparation of β-phenylisoserine and its analogues

ABSTRACT

The present invention relates to new process for the preparation of β-phenylisoserine and its analogues of general formula: ##STR1## which are particularly useful for preparing taxane derivatives which have remarkable antitumour and antileukaemic activities.

This is a continuation of application Ser. No. 08/295,677, filed asPCT/FR93/00224, Mar. 8, 1993, U.S. Pat. No. 5,608,102.

The present invention relates to new process for the preparation ofβ-phenylisoserine and its analogues of general formula: ##STR2## whichare particularly useful for preparing taxane derivatives which haveremarkable antitumour and antileukaemic activities.

In the general formula (I), Ar represents an aryl radical and Rrepresents a hydrogen atom or an alkyl radical containing 1 to 4 carbonatoms, which is optionally substituted by a phenyl radical, or a phenylradical.

Preferably, Ar represents a phenyl or an α- or β-naphthyl radical whichis optionally substituted by one or more atoms or radicals chosen fromhalogen atoms (fluorine, chlorine, bromine, iodine) and alkyl, aryl,aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl,mercapto, formyl, acylamino, aroylamino, alkoxycarbonylamino, amino,alkylamino. dialkylamino, carboxy, alkoxycarbonyl, carbamoyl,dialkylcarbamoyl, cyano, nitro and trifluoromethyl radicals, it beingunderstood that the alkyl radicals and the alkyl portions of the otherradicals contain 1 to 4 carbon atoms and that the aryl radicals arephenyl or α- or β-naphthyl radicals.

More particularly, Ar represents a phenyl radical which is optionallysubstituted by one or more atoms or radicals, which are identical ordifferent, chosen from halogen atoms and alkyl, alkoxy, amino,alkylamino, dialkylamino, acylamino, alkoxycarbonylamino andtrifluoromethyl radicals.

Still more particularly, Ar represents a phenyl radical which isoptionally substituted by a chlorine or fluorine atom or by an alkyl(methyl), alkoxy (methoxy), dialkylamino (dimethylamino) or acylamino(acetylamino) radical.

According to the present invention, the products of general formula (I)are obtained by hydrogenolysis of a product of general formula: ##STR3##in which Ar and R are defined as above and Ph represents a phenylradical which is optionally substituted by one or more atoms or radicalschosen from halogen (fluorine, chlorine, bromine, iodine) and alkoxyradicals containing 1 to 4 carbon atoms, alkylthio radicals containing 1to 4 carbon atoms, amino radicals, alkylamino radicals containing 1 to 4carbon atoms, dialkylamino radicals in which each alkyl portion contains1 to 4 carbon atoms or nitro radicals. More particularly, Ph representsa phenyl radical which is optionally substituted by one or moreradicals, which are identical or different, chosen from methoxy,methylthio, methylamino, dimethylamino or nitro radicals.

Generally, the hydrogenolysis is performed by means of hydrogen in thepresence of a catalyst.

More particularly, a palladium on carbon containing 1 to 10% by weightof palladium or palladium dihydroxide on carbon containing up to 10% byweight of palladium are used as catalyst.

The hydrogenolysis is performed in an organic solvent or a mixture oforganic solvents.

It is particularly advantageous to carry out the procedure in aceticacid optionally combined with an aliphatic alcohol containing 1 to 4carbon atoms. A mixture of acetic acid and methanol is of a very specialinterest.

According to a preferred embodiment of the process, the procedure iscarried out under a hydrogen pressure which may be between 1 and 50bars.

The temperature for carrying out the process is generally between 20°and 80° C. and preferably between 50° and 70° C.

The hydrogen required for the hydrogenolysis may also be provided by acompound which releases hydrogen by chemical reaction or by thermaldecomposition such as ammonium formate.

The product of general formula (II) may be obtained by hydrolysis oralcoholysis of a product of general formula ##STR4## in which Ar and Phare defined as above.

It is particularly advantageous to carry out an alcoholysis by means ofan alcohol of general formula R-OE in which R is defined as above, theprocedure being carried out in an acidic medium.

Preferably, the alcoholysia is performed by means of methanol in thepresence of a strong inorganic acid such as hydrochloric acid.

It is advantageous to perform the alcoholysis at a temperature close tothe reflux temperature of the reaction medium.

The product of general formula (III) may be obtained by saponificationor hydrogenolysis of a product of general formula: ##STR5## in which Arand Ph are defined as above and R₁ represents a group protecting thealcohol functional group in the form of an ester or an ether, followedby separation of the (3R,4S) diastereoisomer of general formula (III)from the other diastereoisomers.

More particularly, R₁ represents an alkyl, phenylalkyl or phenyl radicalor a R'₁ --CO radical in which R'₁ represents an alkyl, phenylalkyl orphenyl radical.

Generally, when the alcohol functional group is protected in the form ofan enter, a saponification is performed by means of an inorganic ororganic base such as ammonium hydroxide, lithium hydroxide, sodiumhydroxide or potassium hydroxide, in a suitable solvent.

An aqueous-organic medium such as a methanol-water or atetrahydrofuran-water mixture is preferably used as solvent. Thereaction is carried out at a temperature of between -10° and +20° C.

Generally, when the alcohol functional group is protected in the form ofan ether, a hydrogenolysis is performed by means of hydrogen, optionallygenerated in situ, for example, by decomposition of ammonium formate, inthe presence of a catalyst such as palladium black containing 1 to 10%palladium (w/w).

The separation of the (3R,4S) diastercoisomer may be performed byselective crystallisation from a suitable organic solvent such as ethylacetate, optionally in the presence of an aliphatic hydrocarbon such ashexane or by chromatography on silica.

The product of general formula (IV) may be obtained by cycloaddition ofan imine of general formula: ##STR6## in which Ar and Ph are defined asabove, onto an acid halide of general formula ##STR7## in which R₁ isdefined as above and X represents a halogen atom such as a bromine orchlorine atom.

Generally, the reaction is carried out at a temperature of between -20°and 50° C., preferably in the vicinity of 0° C., in the presence of abase chosen from tertiary amines (triethylamine, N-methyl-morpholine) orpyridine, in an organic solvent chosen from optionally halogenatedaliphatic hydrocarbons such as methylene chloride or chloroform andaromatic hydrocarbons such as benzene, toluene or xylenes.

The product of general formula (V) may be obtained under the conditionsdescribed by M. Furukawa et al., Chem. Pharm. Bull., 25 (1), 181-184(1977).

The product of general formula (I), in which R represents a hydrogenatom, may also be obtained by saponification of a product of generalformula (I), in which R represents an alkyl radical containing 1 to 4carbon atoms, which is optionally substituted by a phenyl radical, or aphenyl radical.

Generally, the saponification is performed by means of an inorganic basesuch as an alkali metal hydroxide (lithium hydroxide, sodium hydroxide),an alkali metal carbonate or bicarbonate (sodium bicarbonate, potassiumcarbonate) in an aqueous-alcoholic medium such as a methanol-watermixture, the procedure being carried out at a temperature of between 10°and 40° C., preferably close to 25° C.

The acids of general formula (I) are particularly useful for preparingthe taxane derivatives of general formula: ##STR8## in which Ar isdefined as above, R₂ represents a hydrogen atom or an acetyl radical andR₃ represents a phenyl radical which is optionally substituted by one ormore atoms or radicals, which are identical or different, chosen fromhalogen atoms and alkyl, hydroxyl, alkoxy, alkanoyl, alkanoyloxy, nitro,amino, alkylamino, dialkylamino, carbamoyl or trifluoromethyl radicals,the alkyl radicals and the alkyl portions of the other radicalscontaining 1 to 4 carbon atoms, or alternatively R₃ represents a radicalR₄ --O-- in which R₄ represents:

a straight or branched alkyl radical containing 1 to 8 carbon atoms, analkenyl radical containing 3 to 6 carbon atoms, a cycloalkyl radicalcontaining 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6carbon atoms, these radicals being optionally substituted by one or moresubstituents chosen from halogen atoms and hydroxyl radicals, alkyloxyradicals containing 1 to 4 carbon atoms, dialkylamino radicals in whicheach alkyl portion contains 1 to 4 carbon atoms, piperidino radicals,morpholino radicals, 1-piperazinyl radicals (optionally substituted in-4 by an alkyl radical containing 1 to 4 carbon atoms or by aphenylalkyl radical whose alkyl portion contains 1 to 4 carbon atoms),cycloalkyl radicals containing 4 to 6 carbon atoms, alkenyl radicalscontaining 4 to 6 carbon atoms, phenyl radicals, cyano radicals, carbbxyradicals or alkyloxycarbonyl radicals whose alkyl portion contains 1 to4 carbon atoms,

or a phenyl radical which is optionally substituted by one or more atomsor radicals chosen from halogen atoms and alkyl radicals containing 1 to4 carbon atoms or alkyloxy radicals containing 1 to 4 carbon atoms,

or a saturated or unsaturated nitrogen-containing heterocyclyl radicalcontaining 5 or 6 members and optionally substituted by one or morealkyl radicals containing 1 to 4 carbon atoms, which possess remarkableantitumour and antileucemic properties.

The product of general formula (VII) in which Ar represents a phenylradical, R₂ represents an acetyl radical and R₃ represents a phenylradical is known by the name of taxol and that for which Ar represents aphenyl radical, R₂ represents a hydrogen atom and R₃ represents atert-butoxy radical is known by the name of Taxotere.

The taxane derivatives of general formula (VII) may be obtained by theaction of an acid of general formula: ##STR9## in which Ar and R₃ aredefined as above and G₃ represents a group which protects the hydroxidefunctional group such as a methoxymethyl, (1-ethoxy)ethyl,benzyloxymethyl, (β-trimethylsilylethoxy)methyl, tetrahydropyranyl,2,2,2-trichloroethoxymethyl or 2,2,2-trichloroethoxycarbonyl radicaloptionally in the form of a halide, an anhydride or a mixed anhydride,on a taxane derivative of general formula: ##STR10## in which G₁represents a group which protects the hydroxyl functional group such as2,2,2-trichloroethoxycarbonyl or trialkylailyl, dialkylarylsilyl,alkyldiarylsilyl or triarylsilyl radical in which each alkyl portioncontains 1 to 4 carbon atoms and each aryl portion preferably representsa phenyl radical and G₂ represents an acetyl radical or a group whichprotects the hydroxyl functional group such as a2,2,2-trichloroethoxycarbonyl radical, to give a product of generalformula: ##STR11## in which Ar, R₃, G₁, G₂ and G₃ are defined as above,followed by the replacement of the groups G₁, G₂ and G₃ by hydrogenatoms.

Generally, the esterification is performed in the presence of acondensing agent such as a carbodiimide such as dicyclohexylcarbodiimideor a reactive carbonate such as 2-pyridyl carbonate and an activatingagent such as an aminopyridine such as 4-dimethylaminopyridine or4-pyrrolidinopyridine, the procedure being carried out in an organicsolvent such as an aromatic hydrocarbon (benzene, toluene, xylene,ethylbenzene, isopropylbenzene, chlorobenzene), an ether(tetrahydrofuran), a nitrile (acetonitrile) or an ester (ethyl acetate),at a temperature of between 0° and 90° C.

The replacement of the protecting groups G₁, G2 and G₃ with hydrogenatoms is generally performed by is treating with zinc in the presence ofacetic acid at a temperature of between 30° and 60° C. or by means of aninorganic or organic acid such as hydrochloric acid or acetic acid insolution in an aliphatic alcohol containing 1 to 3 carbon atoms in thepresence of zinc when one of the protecting groups represents a2,2,2-trichloroethoxycarbonyl radical or by treating in acidic mediumwhen one of the protecting groups represents a silylated radical.

The acid of general formula (VIII) may be obtained by saponification ofan ester of general formula ##STR12## in which Ar, R₃ and G₃ are definedas above and R' represents an alkyl radical containing 1 to 4 carbonatoms, which is optionally substituted by a phenyl radical, or a phenylradical, by means of an inorganic base such as an alkali metal hydroxide(lithium hydroxide, sodium hydroxide), an alkali metal carbonate orbicarbonate (sodium bicarbonate, potassium carbonate) in anaqueous-alcoholic medium such as a methanol-water mixture, the procedurebeing carried out at a temperature of between 10° and 40° C., preferablyclose to 25° C.

The product of general formula (XI) may be obtained under the usualconditions for the preparation of ethers, and more particularlyaccording to the processes described by J-N. Denis et al., J. Org.Chem., 51, 46-50 (1986) from the product of general formula: ##STR13##in which Ar, R₃ and R' are defined as above.

The product of general formula (XII) may be obtained by the action of abenzoyl halide whose phenyl nucleus may be optionally substituted or bythe action of a product of general formula:

    R.sub.4 --O--CO--X                                         (XIII)

in which R₄ is defined as above and X represents a halogen atom(fluorine, chlorine) or a residue --O--R₄ or --O--CO--OR₄, on a productof general formula (I) in which R represents an alkyl radical containing1 to 4 carbon atoms, which is optionally substituted by a phenylradical, or a phenyl radical.

Generally, the procedure is carried out in an organic solvent such asmethylene chloride in the presence of an inorganic base such as sodiumbicarbonate.

The product of general formula (XII) in which Ar represents a phenylradical substituted by a cyano radical may be obtained by dehydration ofa product of general formula (XII) in which Ar represents a phenylradical substituted by a carbamoyl radical and the alcohol functionalgroup is preferably protected by a silylated radical, followed by thereplacement of the protecting group by a hydrogen atom.

The dehydration may be generally performed according to the usualmethods for the preparation of nitriles from amides. For example,phosphorus oxychloride in pyridine is used.

The taxane derivatives of general formula (VII) may also be obtained byfirst converting the product of general formula (XII) to an oxazolidinederivative of general formula ##STR14## in which Ar and R₃ are definedas above and R₅ and R₆, which are identical or different, represent ahydrogen atom or an alkyl radical containing 1 to 4 carbon atoms or anaryl radical, preferably a phenyl radical optionally substituted by oneor more alkoxy radicals containing 1 to 4 carbon atoms, or alternativelyR₅ represents an alkoxy radical containing 1 to 4 carbon atoms or atrihalomethyl radical such as trichloromethyl and R₆ represents ahydrogen atom, or alternatively R₅ and R₆ together form with the carbonatom to which they are attached a ring having 4 to 7 members, then byesterifying the taxane derivative of general formula (IX) by means ofthe acid of general formula (XIV) to give a product of general formula:##STR15## in which Ar, G₁, G₂, R₃, R₅ and R₆ are defined as above, whichis converted to the taxane derivative of general formula (VII) bypassing, when R₅ and R₆, which are identical or different, represent analkyl radical containing 1 to 4 carbon atoms, or an aryl radical,preferably an optionally substituted phenyl radical, or alternatively R₅represents a trihalomethyl radical or a phenyl radical substituted by atrihalomethyl radical and R₆ represents a hydrogen atom, oralternatively R₅ and R₆ form together with the carbon atom to which theyare attached a ring having 4 to 7 members, via a taxane derivative ofgeneral formula ##STR16## which is acylated by means of benzoyl chlorideor of a product of general formula (XIII), the procedure being 15carried out for example under the conditions described in PCTApplication WO 9209589, before obtaining a product of general formula:##STR17## whose protecting groups G₁ and G₂ are replaced by hydrogenatoms under the conditions described above.

The following examples illustrate the invention.

EXAMPLE 1

To 0.91 g of a 3% dispersion of palladium on activated carbon powder,are added a solution of 1.6 g of methyl (2R,3S)-2-hydroxy-3-(S)-1-phenyl!ethylamino-3-phonylpropionate in a mixture of 30 cm³ ofmethanol and 10 cm³ of acetic acid. The reaction mixture is heated to atemperature of 65° C. for 4 hours, with stirring and at a pressure of2600 kPa (26 bars) of hydrogen, in a 250-cm³ stainless steel autoclave.The reaction mixture is then cooled to a temperature close to 20° C. andfiltered over sintered glass containing celite. The sintered glass iswashed with 3 times 10 cm³ of methanol and the filtrates are pooled andthen concentrated to dryness under reduced pressure (2.7 kPa) at atemperature close to 40° C. The residue is supplemented with 40 cm³ ofdistilled water and the solution obtained is alkalinised to a pH closeto 7 by addition of 8 cm³ of a 7.5N aqueous solution of sodium hydroxideand then extracted with 4 times 60 cm³ of dichloromethane. The organicphases are pooled, dried over magnesium sulphate, filtered and thenconcentrated to dryness under reduced pressure (2.7 kPa) at 40° C. 0.74g of white crystals are thus obtained which are recrystallised from 10cm³ of a mixture of diisopropyl ether and ethyl acetate (70-30 byvolume) to give 0.54 g of methyl(2R,3S)-3-amino-2-hydroxy-3-phenylpropionate in the form of whitecrystals with a melting point of 1010C and whose characteristics are asfollows:

specific rotation: α!_(D) ^(2D) =-19° (c=0.51; methanol)

NMR spectrum (300 MHz; CDCl₃) δ(ppm): 2.22 (m, 3H: --NH₂ and OH); 3.81(a, 3H: --COOCH₃); 4.32 (s, 2H: --CHOH and --CHNH₂); 7.20 to 7.5 (m, 5H:--C₆ H₅).

Methyl (2R,3S)-2-hydroxy-3- (S)-l-phenyl!-ethylamino-3-phenylpropionatemay be prepared in the following manner:

A solution of 0.8 g of (3R,4S)-3-hydroxy-4-phenyl-1-(S)-l-phenyllethyl-2-azetidinone in a mixture of 30 cm³ of methanol and6 cm3 of a 6N aqueous solution of hydrochloric acid is refluxed (65° C.)for 20 hours, then cooled to a temperature close to 20°C. andconcentrated to dryness under reduced pressure (2.7 kPa) at atemperature close to 40°C. The residue is supplemented with 20 cm³ ofdistilled water and alkalinised up to a pH close to 7 by addition of a7.5N aqueous solution of sodium hydroxide and then extracted with 3times 25 cm³ of dichloromethane. The organic phases are pooled, driedover magnesium sulphate, filtered and then concentrated to dryness underreduced pressure (2.7 kPa) at 40°C. 0.74 g of methyl(2R,3S)-2-hydroxy-3- (S)-1-phenyl!ethylamino-3-phenylpropionate is thusobtained in the form of a pale yellow oil whose characteristics are asfollows:

specific rotation: α!_(D) ²⁰ =-22.7° C. (c=1.00; methanol)

NMR spectrum (200 MHz; CDCl₃)

δ(ppm): 1.34 (d,3H, J=7 Hz: -CCH₃); 2.7 (m, 2H: --CNHC--and --OH); 3.71(q, 1H, J=7 Hz: --CHNK--); 3.84 (s, 3H:

--COOCH₃); 4.2 (d, 1H, J=4 Hz: --CHOH--); 4.35 (d, 1H, J=4 Hz:--CHNH--); 7.20 to 7.45 (m, 5H: --C₆ H₅) .

(3R,4S)-3-hydroxy-4-phenyl-1- (S)-1-phenyl!-ethyl-2-azetidone may beprepared according to one of the following methods:

1) To a mixture of 120 cm³ of a 1N aqueous solution of potassiumhydroxide and 90 cm³ of tetrahydrofuran, is added over 35 minutes, withstirring and at a temperature close to 0°C., a solution of 3.3 g of amixture in a 75/25 molar ratio of the two diastereoisomers of3-acetoxy-4-phenyl-1- (S)-1-phenyl!ethyl-2-azetidinone, form A and formB, in 120 cm³ of tetrahydrofuran. When the addition is completed, thereaction medium is stirred at a temperature close to 0°C. for 1 hour andthen supplemented with 120 cm³ of a saturated aqueous solution of sodiumhydrogen carbonate and 100 cm³ of distilled water. The aqueous phase isseparated by decantation and reextracted with 3 times 100 cm³ of ethylacetate. The organic phases are pooled, dried over magnesium sulphate,filtered and then concentrated to dryness under reduced pressure (2.7kPa) at 40°C. 2.8 g of white crystals are thus obtained which arerecrystallised from 35 cm³ of a mixture of ethyl acetate and hexane(80-20 by volume) to give 1.92 g of (3R,4S)-3-hydroxy-4-phenyl-1-(S)-1-phenyl!ethyl-2-azetidinone in the form of white crystals with amelting point of 162° C. and whose characteristics are as follows:

specific rotation: α!_(D) ²⁰ =+132° C. (c=1.08; methanol)

NMR spectrum (200 MHz; CDCl₃)

δ(ppm): 1.41 (d, 3H, J=7 Hz: --CHCH₃); 2.36 (d, 1H, J=8.5 Hz: --OH);4.58 (d, 1H, J=4.5 Hz: --CHC₄ H₅); 4.90 (dd, 1H, J=8.5 Hz and 4.5 Hz:--CHOH--); 5.06 (q, 1H, J=7 Hz: --CHCH₃); 7.20 to 7.50 (m, 5H : --C₆ H₅).

The mixture of the A form and of the B form of 3-acetoxy-4-phenyl-1-(S)-1-phenyl!ethyl-2-azetidone may be prepared in the following manner:

To a solution of 14.63 g of (S)-N-benzylidene(1-phenylethylamine) in 180cm³ of chloroform, are added, with stirring and at a temperature closeto 20°C., 19.6 cm³ of triethylamine, then the reaction mixture is cooledto a temperature close to -20°C. and 5.17 cm³ of 2-acetoxyacetylchloride in 90 cm³ of chloroform are added dropwise, over 75 minutes andwhile this temperature is maintained. The solution maintained is stirredfor 16 hours at a temperature close to 20° C. and then supplemented with300 cm³ of a 2.7N aqueous solution of hydrochloric acid. The organicphase is separated by decantation, washed with twice 300 cm3 ofdistilled water and then with 300 cm³ of a saturated aqueous solution ofsodium hydrogen carbonate, dried over magnesium sulphate, filtered andthen concentrated to dryness under reduced pressure (2.7 kPa) at 40° C.16.5 g of a brown oil are thus obtained which are purified bychromatography on 800 g of silica (0.04-0.063 mm) contained in a columnwith a diameter of 6.8 cm eluent:cyclohexane-ethyl acetate (70-30 byvolume)!, recovering 22 cm³ fractions. *Fractions 100 to 153 are pooledand concentrated to dryness under reduced pressure (0.27 kPa) at 40° C.10.65 g of a mixture in a 75/25 molar ratio of the two diastereoisomersof 3-acetoxy-4-phenyl-1- (S)-1-phenyl!-ethyl-2-azetidinone are thusobtained in the form of a yellow oil.

(S)-N-benzylidene(1-phenylethylamine) may be prepared according to themethod described by M. Furukawa et al., Chem. Pharm. Bull., 1977, 25(1),181-184.

2) By carrying out the procedure as above, but starting with 100 mg of amixture in a 70/30 molar ratio of the two diastereoisomeres of3-isobutyryloxy-4-phenyl-1- (S)-1-phenyl!ethyl-2-azetidinone; form A andform B, 82 mg of (3R,4S)-3-hydroxy-4-phenyl-1-(S)-1-phenyl!ethyl-2-azetidinone are obtained in the form of whitecrystals with a melting point of 162° C. whose physical characteristicsare identical to those of the product obtained above.

The mixture of the A and B forms of 3-isobutyryloxy-4-phenyl-1-(S)-1-phenyl!ethyl-2-azetidinone may be prepared by carrying out theprocedure as above but starting with 1.91 g of(S)-N-benzylidene(1-phenylethylamine) and 1 g of 2-isobutyryloxyacetylchloride. 1.27 g of a mixture in a 70/30 molar ratio of the twodiasteraoisomers of 3-isobutyryloxy-4-phenyl-1-(S)-1-phenyl!ethyl-2-azetidinone are obtained in the form of a yellowoil. 2-isobutyryloxyacetyl chloride may be prepared in the followingmanner:

To a solution of 5 g of glycolic acid in 100 cm³ of dichloromethane,maintained under an argon atmosphere, are added, with stirring and at atemperature close to 20°C., 18.3 cm3 of triethylamine and then thereaction mixture is cooled to a temperature close to 5° C. and 13.8 cm3of isobutyryl chloride are added dropwise over 30 minutes while thistemperature is maintained. The solution obtained is stirred for 3 hoursat a temperature close to 20° C. The precipitate which appears isseparated by filtration and washed with twice 10 cm³ of dichloromethane.The pooled filtrates are washed with 60 cm³ of a saturated aqueoussolution of ammonium chloride, then with 30 cm³ of a saturated aqueoussolution of sodium chloride, dried over magnesium sulphate, filtered andthen concentrated to dryness under reduced pressure (2.7 kPa) at 40° C.13 g of a yellow oil are thus obtained to which are added 24 cm³ ofsulphinyl chloride. The solution obtained is refluxed for 2.5 hours andthen distilled under reduced pressure (0.07 kPa; 0.5 mmHg). 3.4 g of2-isobutyryloxyacetyl chloride are thus obtained in the form of acolourless liquid which distils off at 45°-50° C., at a pressure of 0.07kPa.

3) To 43 mg of a 10% dispersion of palladium on carbon powder, are addeda solution of 91 mg of a mixture in a 60/40 molar ratio of the twodiastereoisomers of 3-benzyloxy-4-phenyl-1-(S)-1-phenyl!ethyl-2-azetidinone, form A and form B, in 6 cm³ ofmethanol and then 32 mg of ammonium formate. The reaction mixture ismaintained stirring and under an argon atmosphere for 72 hours at atemperature close to 20° C., then 56 mg of a 10% dispersion of palladiumand 128 mg of ammonium formate are added. The reaction mixture ismaintained stirring at this temperature for 26 hours. The reactionmixture is then filtered on sintered glass containing celite. Thesintered glass is washed with 3 times 5 cm³ of dichloromethane and thenthe pooled-filtrates are concentrated under reduced pressure (2.7 kPa)at a temperature close to 40° C. 70 mg of white crystals are thusobtained which are purified by chromatography on silica gel deposited onplates (gel 1 mm thick; 20 times 20 cm plate) in 10 mg fractions. Afterlocation under U.V. rays of the zone corresponding to the desiredproduct, this zone is scraped and the silica is recovered and thenwashed on sintered glass with 10 times 5 cm3 of dichloromethane and with5 times 2 cm3 of methanol. The filtrates are pooled and concentrated todryness under reduced pressure (0.27 kPa) at 40°C. 28 mg of(3R,4S)-3-hydroxy-4-phenyl-1- (S)-1-phenyl!ethyl-2-azetidinone are thusobtained in the form of white crystals with a melting point of 162° C.whose physical characteristics are identical to those of the productobtained above.

The mixture of the A and B forms of 3-benzyloxy-4-phenyl-1-(S)-1-phenyl!ethyl-2-azetidinone may be prepared by carrying out theprocedure as above but starting with 2.0 g of(S)-N-benzylidene(1-phenyl-ethylamine) and 1.38 g of 2-benzyloxyacetylchloride. 1.25 g of a mixture in a 60/40 molar ratio of the twodiastereoisomers of 3-benzyloxy-4-phenyl-1-(S)-1-phenyl!ethyl-2-azetidinone are thus obtained in the form of ayellow oil.

EXAMPLE 2

To a solution of 0.53 g methyl(2R,3S)-3-amino-2-hydroxy-3-phenylpropionate in 8 cm³ ofdichloromethane, maintained under an argon atmosphere, are added 0.25 gof sodium hydrogen carbonate and then, dropwise, at a temperature closeto 20° C., a solution of 0.73 g of di-tert-butyl dicarbonate in 2 cm³ ofdichloromethane. The solution obtained is stirred for 72 hours at atemperature close to 20° C. and then supplemented with 20 cm³ ofdistilled water. The aqueous phase is separated by decantation and thenreextracted with twice 10 cm³ of dichloromethane. The organic phases arepooled, dried over magnesium sulphate, filtered and then concentrated todryness under reduced pressure (2.7 kPa) at 40° C.

0.45 g of methyl(2R,3S)-3-tert-butoxy-carbonylamino-2-hydroxy-3-phenylpropionate arethus obtained after crystallisation from diisopropyl ether, in the formof white crystals with a melting point of 135° C. whose physicalcharacteristics are identical to those described in European Patent EP0,414,610:

specific rotation: α!_(D) ²⁰ =-2.6° (c=1; methanol) α!_(D) ²⁰ =-7.4°(c=1.03; chloroform)

NMR spectrum (200 MHz; CDCl₃) δ(ppm): 1.42 (s, 9H: --NHCOOC(CH₃)₃); 3.16(d, 1H, J=5 Hz: --OH); 3.87 (s, 3H: --COOCH₃); 4.48 (m, 1H: --CHOH);5.22 (broad d, 1H, J=10.5 Hz: --CHNHCOOC(CH₃)₃); 5.39 (d, 1H, J=10.5 Hz:--NHCOOC(CH₃)₃); 7.20 to 7.45 (m, 5H: --C₆ H₅).

The product thus obtained may be converted to Taxotere under theconditions described in European Patent EP 0,336,841.

EXAMPLE 3

To 1 g of a 10% dispersion of palladium on activated carbon powder, isadded a solution of 5.05 g of methyl (2R,3S)-2-hydroxy-3-(S)-1-phenyllethylamino-3-(4-fluorophenyl)propionate in a mixture of 95cm³ of methanol and 32 cm³ of acetic acid. The reaction mixture isheated at a temperature of 65° C. for 5 hours, with stirring and at apressure of 2300 kPa (23 bars) of hydrogen, in a 1000-cm³ stainlesssteel autoclave. The reaction mixture is then cooled to a temperatureclose to 20° C. and filtered on sintered glass containing celite. Thesintered glass is washed with 3 times 30 cm³ of methanol and thefiltrates are pooled and then concentrated to dryness under reducedpressure (2.7 kPa) at a temperature close to 40° C.

The residue is supplemented with 50 cm³ of distilled water and thesolution obtained is alkalinised to a pH close to 7 by addition of a7.5N aqueous solution of sodium hydroxide and then extracted with 3times 80 cm³ of dichloromethane. The organic phases are pooled, driedover magnesium sulphate, filtered and then concentrated to dryness underreduced pressure (2.7 kPa) at 40° C. 2.45 g of methyl(2R,3S)-3-amino-2-hydroxy-3-(4-fluoro-phenyl)propionate are thusobtained in the form of cream-coloured crystals with a melting point of105° C. whose physical characteristics are as follows:

NMR spectrum: (300 MHz; CDCl₃ +εCD₃ COOD; δ in ppm). 3.56 (a, 3H:--COOCH3); 4.61 and 4.69 (2 mt, 1H each: --CHOH and --CHNH₂); 7.06 t,J=8.5 Hz, 2H: --C₆ H₄ F(--H3 and --H5)!; 7.46 dd, J=8.5 and 6.5 Hz, 2H:--C₆ H₄ F(--H2 and --H6)!.

Methyl (2R,3S)-2-hydroxy-3-(S)-1-phenyl!-ethylamino-3-(4-fluorophenyl)propionate may be prepared inthe following manner:

A solution of 5.45 g of (3R,4S)-3-hydroxy-4-(4-fluorophenyl)-1-(S)-1-phenyllethyl-2-azetidinone in a mixture of 175 cm³ of methanol and35 cm³ of a 6N aqueous solution of hydrochloric acid is refluxed (65°C.) for 18 hours, then cooled to a temperature close to 20° C. andconcentrated to dryness under reduced pressure (2.7 kPa) at atemperature close to 40° C. The residue is supplemented with 150 cm³ ofdistilled water and alkalinised to a pH close to 7 by addition of a 7.5Naqueous solution of sodium hydroxide and then extracted with 3 times 150cm³ of dichloromethane. The organic phases are pooled, dried overmagnesium sulphate, filtered and then concentrated to dryness underreduced pressure (2.7 kPa) at 40° C. 5.08 g of methyl(2R,3S)-2-hydroxy-3-(S)-1-phenyl!ethylamino-3-(4-fluorophenyl)-propionate are thus obtainedin the form of a pale yellow oil whose physical characteristics are asfollows:

NMR spectrum: (300 MHz; CDCl₃ ; δ in ppm). 1.26 (d, J=7 Hz, 3H:--CHCH₃); 3.60 (q, J=7 Hz, 1H: --CHCH₃) ; 3.79 (s, 3H: --COOCH₃); 4.12and 4.19 (2d, J=3 Hz, 1H each: --CHOH and --CHNH--); 7.00 t, J=8.5 Hz,2H: --C₆ H₄ F(--H3 and --H5)!; 7.10 to 7.40 mt, 7H: --C₆ H₅ and --C₆ H₄F(--H2 and --H6)!.

(3R,4S)-3-Hydroxy-4-(4-fluorophenyl)-1- (S)-1-phenyl!ethyl-2-azetidinonemay be prepared in the following manner:

To a mixture of 470 cm3 of a 1N aqueous solution of potassium hydroxideand 250 cm³ of tetrahydrofuran, is added over 75 minutes, with stirringand at a temperature close to 0° C., a solution of 12.4 g of a mixturein a 75/25 molar ratio of the two diastereo-isomers of3-acetoxy-4-(4-fluorophenyl)-1-((s)-1-phenyl!ethyl-2-azetidinone, form Aand form B, in 300 cm³ of tetrahydrofuran. When the addition iscompleted, the reaction medium is stirred at a temperature close to 0°C. for 2.5 hours and then supplemented with 250 cm³ of a saturatedaqueous solution of sodium hydrogen carbonate. The aqueous phase isseparated by decantation and rextracted with 3 times 250 cm³ of ethylacetate. The organic phases are pooled, dried over magnesium sulphate,filtered and then concentrated to dryness under reduced pressure (2.7kPa) at 40° C.

10.1 g of white crystals are thus obtained which are recrystallised from55 cm³ of a mixture of ethyl acetate and hexane (80-20 by volume) togive 5.45 g of C3R,4S)-3-hydroxy-4-(4-fluorophenyl)-1-(S)-1-phenyllethyl-2-azetidinone in the form of white crystals with amelting point of 155° C. and whose physical characteristics are asfollows:

NMR spectrum: (300 MHz; CDCl₃ ; δ in ppm). 1.29 (d, J=7.5 Hz, 3H:--CHCH₃); 3.59 (broad s, 1H: --OH); 4.40 (d, J=3.5 Hz, 1H: --CHC₆ H₄ F);4.52 (broad d, J=3.5 Hz, 1H: --CHOH); 4.90 (q, J=7.5 Hz, 1H: --CHCH₃);6.96 t, J=8.5 Hz, 2H: --C₆ H₄ F(--H3 and --H5)!; 7.00 to 7.30 mt, 7H:--C₆ H₅ and --C₆ H₄ F(--H2 and --H6)!.

The mixture of the A and B forms of 3-acetoxy-4-(4-fluorophenyl)-1-(S)-1-phenyllethyl-2-azetidinone may be prepared in the followingmanner:

To a solution of 16.8 g of(S)-N-(4-fluoro)-benzylidene(1-phenylethylamine) in 220 cm³ ofchloroform, are added, with stirring and at a temperature close to 20°C., 20.8 cm³ of triethylamine, then the reaction mixture is cooled to atemperature close to -20° C. and a solution of 8.2 cm³ of2-acetoxy-acetyl chloride in 80 cm³ of chloroform are added dropwise,over 1 hour while this temperature is maintained. The solution obtainedis stirred for 16 hours at a temperature close to 20° C. and thensupplemented with 200 cm³ of a 2.7N aqueous solution of hydrochloricacid. The organic phase is separated by decantation, washed with twice200 cm³ of distilled water and then with 200 cm³ of a saturated aqueoussolution of sodium hydrogen carbonate, dried over magnesium sulphate,filtered and then concentrated to dryness under reduced pressure (2.7kPa) at 40° C. 19.7 g of a brown oil are thus obtained which arepurified by chromatography on 1100 g of silica (0.04-0.063 mm) containedin a column with a diameter of 8.5 cm eluent: cyclohexane-ethyl acetate(70-30 by volume)!, collecting 60-cm3 fractions. The fractionscontaining only the desired product are pooled and concentrated todryness under reduced pressure (0.27 kPa) at 40° C. 13.7 g of a mixturein a 75/25 molar ratio of the two diastereoisomers of3-acetoxy-4-(4-fluorophenyl)-1-((S)-1-phenyl ethyl-2-azetidinone arethus obtained in the form of a yellow oil.

(S) -N- (4-Fluoro)benzylidene(l-phenylethyl-amine) may be prepared inthe following manner:

To a solution of 12.4 g of 4-fluorobenzalde-hyde in 80 cm3 ofdichloromethane, are added, with stirring and at a temperature close to20° C., 13 cm³ of (S)-1-phenylethylamine and 6 g of a 4 Å molecularsieve. The reaction mixture is stirred for 16 hours at a temperatureclose to 20° C. and then filtered on sintered glass containing celite.The sintered glass is washed with three times 20 cm³ of dichloromethaneand the filtrates are pooled and then concentrated to dryness underreduced pressure (2.7 kPa) at a temperature close to 40° C. 18.3 g of(S)-N-(4-fluoro)benzylidene(I-phenylethylamine) are thus obtained in theform of an opalescent oil.

EXAMPLE 4

To a solution of 2.4 g of methyl(2R,3S)-3-amino-2-hydroxy-3-(4-fluorophenyl)propionate in 60 cm³ ofdichloromethane, maintained under an argon atmosphere, are added 0.95 gof sodium carbonate and then, dropwise, at a temperature close to 20°C., a solution of 2.46 g of di-tert-butyl dicarbonate in 20 cm³ ofdichloromethane. The solution obtained is stirred for 16 hours at atemperature close to 20° C. and then supplemented with 100 cm³ ofdistilled water. The aqueous phase is separated by decantation and thenreextracted with twice 50 cm3 of dichloromethane. The organic phases arepooled, dried over magnesium sulphate, filtered and then concentrated todryness under reduced pressure (2.7 kPa) at 40° C. 2.35 g of methyl(2R,3S)-3-tert-butoxy-carbonylamino-2-hydroxy-3-(4-fluorophenyl)propionateare thus obtained after recrystallisation from diisopropyl ether in theform of white crystals with a melting point of 125° C. which isconverted to 4-acetoxy-2a-benzoyloxy-54,20-epoxy-1A,7,710#-trihydroxy-9-oxo-11-taxen-13a-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-(4-fluorophenyl)propionate,the procedure being carried out under the conditions described inEuropean Patent EP 0,336,841.

EXAMPLE 5

By carrying out the procedure under the conditions described in Example1, methyl(2R,3S)-3-amino-2-hydroxy-3-(4-trifluoromethylphenyl)propionate isprepared in the form of cream-coloured crystals with a melting point of134° C. by passing via the following intermediates:

methyl (2R,3S)-2-hydroxy-3-(S)-1-phenyllethylamino-3-(4-trifluoromethylphenyl)propionate in theform of a yellow oil,

(3R,4S)-3-hydroxy-4-(4-trifluoromethylphenyl)-1-(S)-1-phenyllethyl-2-azetidinone in the form of white crystals with amelting point of 165° C.,

the mixture of the A and B forms of3-acetoxy-4-(4-trifluoromethylphenyl)-1-(S)-1-phenyl!ethyl-2-azetidinone in the form of a white paste,

(S) -N- (4-trifluoromethyl)benzylidene(1-phenylethylamine) in the formof white crystals with a melting point below 50° C.

EXAMPLE 6

By carrying out the procedure as in Example 2, but starting with 2.73 gof methyl(2R,3S)-3-amino-2-hydroxy-3-(4-trifluoromethylphernyl)propionate, 2.43 gof methyl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-(4-trifluoromethylphenyl)propionateare obtained in the form of white crystals with a melting point of 120°C. whose physical characteristics are as follows:

NMR spectrum: (300 MHz; DMSO-d₆ ; δ in ppm). 1.40 s, 9H: --NHCOOC(CH₃)₃!; 3.62 (s, 3H: --COOCH₃); 4.40 (mt, 1H: --CHOH); 5.08 (dd, J=11 and 4.5Hz, 1H: --CHNHCOOC(CH₃)₃ !; 5.65 (d, J=6.5 Hz, 1H: --OH); 7.40 d, J=11Hz, 1H: --NHCOOC(CH₃)₃ 3; 7.59 and 7.72 (2d, J=8.5 Hz, 2H each: --C₆ H₄CF₃ (--H3, --H5 and --H2, --H6)!.

The product thus obtained is converted to4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,7β,10β-trihydroxy-9-oxo-11-taxen-13α-yl(2R,3S)-3-tert-butoxycarbonyl-amino-2-hydroxy-3-(4-trifluoromethylphenyl)propionate,the procedure being carried out under the conditions described inEuropean Patent EP 0,336,841.

EXAMPLE 7

By carrying out the procedure under the conditions described in Example1, methyl (2R,3S)-3-amino-2-hydroxy-3-(4-dimethylaminophenyl)propionateis prepared in the form of cream-coloured crystals with a melting pointof 119° C. by passing via the following intermediates:

methyl (2R,3S)-2-hydroxy-3-(S)-1-phenyllethylamino-3-(4-dimethylaminophenyl)propionate in the formof white crystals with a melting point of 122° C.,

(3R,4S)-3-hydroxy-4-(4-dimethylaminophenyl)-1-(S)-1-phenyl!ethyl-2-azetidinone in the form of white crystals with amelting point of 220° C.,

the mixture of the A and B forms of3-acetoxy-4-(4-dimethylaminophenyl)-1- (S)-1-phenyl!lethyl-2-azetidinonein the form of white crystals with a melting point of 136° C.,

(S) -N- (4-dimethylamino)benzylidene(1-phenylethylamine) in the form ofwhite crystals with a melting point below 50° C.

EXAMPLE 8

By carrying out the procedure as in Example 2, but starting with 0.8 gof methyl (2R,3S)-3-amino-2-hydroxy-3-(4-dimethylaminophenyl)propionate,0.82 g of methyl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-(4-dimethylaminophenyl)propionateis obtained in the form of white crystals with a melting point of 120°C. whose physical characteristics are as follows: NMR spectrum: (200MHz; DMSO-d6; δ in ppm). 1.39 s, 9H: --NHCOOC(CH₃)₃ !; 2.90 s, 6H:--N(CH₃)₂ !; 3.59 (s, 3H: --COOCH₃); 4.21 (dd, J=7.5 and 4.5 Hz, 1H:--CHOH); 4.81 dd, J=9.5 and 4.5 Hz, 1H: --CHNHCOOC(CH₃)₃ !; 5.47 (d,J=7.5 Hz, 1K: --OH); 7.02 d, J=9.5 Hz, 1H: --NHCOOC(CH₃)₃ ; 6.66 d,J=8.5 Hz, 2H: --C₆ H₄ N(CH₃)₂ (--H3 and --H5)!; 7,12 2d, J=8.5 Hz, 2H:--C₆ H₄ N(CH₃)₂ (--H2 and --H6)!.

The product thus obtained is converted to4-acatoxy-2a-banzoyloxy-5β,20-epoxy-l,7β,10β-trihydroxy-9-oxo-1;-taxen-13a-yl(2R,3S)-3-tert-butoxy-carbonylamino-2-hydroxy-3-(4-dimethylaminophenyl)-propionate,the procedure being carried out under the conditions described inEuropean Patent EP 0,336,841.

EXAMPLE 9

To 2.1 g of a 20% dispersion of palladium dihydroxide on activatedcarbon powder, is added a solution of 5.5 g of methyl(2R,3S)-3-(4-carbamoylphenyl)-2-hydroxy-3-(S)-1-phenyl!-ethylaminopropionate in a mixture of 100 cm³ of methanoland 3 cm³ of acetic acid. The reaction mixture is maintained stirringfor 60 hours at a temperature close to 20° C. and at a pressure of 120kPa (1.2 bars) of hydrogen. The reaction mixture is then filtered onsintered glass containing celite. The sintered glass is washed with 3times 15 cm³ of methanol and the filtrates are pooled and thenconcentrated to dryness under reduced pressure (2.7 kPa) at atemperature close to 40° C. The crystals recovered are washed onsintered glass with 20 cm³ of diethyl ether. 4.6 g of methyl(2R,3S)-3-amino-3-(4-carbamoylphenyl)-2-hydroxypropionate are thusobtained in the form of white crystals with a melting point of 206° C.and whose characteristics are as follows:

NMR spectrum: (300 MKz; DMSO-d₆ ; δ in ppm). 1.90 (s, 3H: CH₃ COO--);3.60 (s, 3H: --COOCH₃); 4.13 (limiting ab, 2H: --CHOH and --CHNH₃); 7.30and 7.95 (2s, 1H each: --CONH₂); 7.40 (d, J=8.5 Hz, 2H: --C₆ H₄ CONH₂(--H2 and --H6)!; 7.80 (d, J=8.5 Hz, 2H: --C₆ H₄ CONH₂ (--H3 and -H5)!.

Methyl(2R,3S)-3-(4-carbamoylphenyl)-2-hydroxy-3-((S)-1-phenyl!ethylaminopropionatemay be prepared in the following manner:

To a solution of 10 g of(3R,4S)-4-(4-cyano-phenyl)-3-hydroxy-1-((S)-1-phenyl!othyl-2-azetidinonein 100 cm³ of acetic acid, are added 10.9 g of mercuric acetate. Thereaction medium is refluxed for 5 hours, then cooled to a temperatureclose to 20° C. and concentrated to dryness under reduced pressure (2.7kPa) at a temperature close to 40° C. The residue is supplemented with150 cm³ of methanol and concentrated to dryness under reduced pressure(2.7 kPa) at a temperature close to 40° C. 300 cm³ of methanol are addedto the residual solid and a gaseous stream of anhydrous hydrochloricacid is injected, with stirring, into the reaction medium, at atemperature close to 40° C. for 1.5 hours. The reaction medium isconcentrated to dryness under reduced pressure (2.7 kPa) at 40° C. andthen poured into a mixture of 300 cm³ of ethyl acetate, 300 cm³ ofdistilled water and 100 cm³ of a saturated aqueous solution of sodiumhydrogen carbonate. The aqueous phase is separated by decantation andreextracted with twice 250 cm³ of ethyl acetate. The organic phases arepooled, washed with twice 150 cm³ of a 3% aqueous solution of sodiumsulphide and then with twice 100 cm3 of distilled water, dried overmagnesium sulphate, filtered and then concentrated to dryness underreduced pressure (2.7 kPa) at 40° C. The crystals recovered are washedon sintered glass with 20 cm³ of diethyl ether. 5.5 g of methyl(2R,3S)-3-(4-carbamoylphenyl)-2-hydroxy-3-(S)-1-phenyllethylaminopropionate are thus obtained in the form of whitecrystals with a melting point of 130° C. whose characteristics are asfollows:

NMR spectrum : (300 MHz; CDCl₃ ; δ in ppm) 1.30 (d, J=7 Hz, 3H:--CHCH₃); 3.65 (q, J=7 Hz, 1H: --CHCH₃); 3.85 (s, 3H: --COOCH3); 4.25and 4.35 (2d, J=3.5 Hz, 1H each: --CHOH-- and --CHNH--); 5.97 and 6.17(2 unresolved complexes, 1H each: --CONH₂); 7.20 to 7.40 (mt, 5H: C₆ H₅); 7.41 d, J=8.5 Hz, 2H: --C₆ H₄ CONH₂ (H2 and H6)!; 7.81 d, J=8.5 Hz,2H: --C₆ H₄ CONH₂ (H3 and H5)!. (3R,4S)-4-(4-Cyanophenyl)-3-hydroxy-1-(S)-1-phenyl!ethyl-2-azetidinone may be prepared in the followingmanner:

Into a solution of 55.3 g of a mixture in a 65/35 molar ratio of the twodiastereoisomers of 3-acetoxy-4-(4-cyanophenyl)-1-(S)-1-phenyl!ethyl-2-azetidinone, form A and form B, in 550 cm³ ofmethanol, is injected, with stirring, a gaseous stream of anhydrousammonia at a temperature close to 0° C. for 3 hours. The reaction mediumis concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. 41g of white crystals are obtained which are recrystallised from a mixtureof 280 cm³ of ethyl acetate and 70 cm³ of diethyl ether. The crystalsobtained are recrystallised a second time from 160 cm3 of ethyl acetateand then a third time from 100 cm³ of acetonitrile. 10 g of(3R,4S)-4-(4-cyanophenyl)-3-hydroxy-1- (S)-1-phenyl!ethyl-2-azetidinoneare thus obtained in the form of white crystals with a melting point of139° C. and whose characteristics are as follows:

NMR spectrum: (300 MHz; CDCl₃ ; δ in ppm). 1.39 (d, J=7.5 Hz, 3H:--CHCH,3); 3.89 (d, J=6.5 Hz, 1H: --OH); 4.54 (d, J=4 Hz, 1H: --CH6H₅) ;4.96 (dd, J=6.5 and 4 Hz, 1H: --CHOH); 4.96 (q, J=7.5 Hz, 1H: --CHCH₃);7.10 to 7.40 (mt, 5H: --C₆ H₅); 7.43 Ed, J=8.5 Hz, 2H: --C₆ H₄ CN(--H2and --H6)!; 7.66 d, J=8.5 Hz, 2H: --C₆ H₄ CN(--H³ and --H5)!.

The mixture of the A and B forms of 3-acetoxy-4-(4-cyanophenyl)-1-(S)-1-phenyl!ethyl-2-azetidinone may be prepared in the followingmanner:

To a solution of 56.1 g of(S)-N-(4-cyano)-benzylidene(1-phenylethylamine) in 600 cm³ ofchloroform, are added, with stirring and at a temperature close to 0°C., 47.6 cm³ of triethylamine and then, dropwise, over 3 hours and whilethis temperature is maintained, a solution of 18.6 cm³ of2-acetoxy-acetyl chloride in 500 cm³ of chloroform. The solutionobtained is stirred for 16 hours at a temperature close to 20° C. andthen supplemented with 250 cm³ of distilled water. The organic phase isseparated by decantation, washed with 250 cmu of distilled water, driedover magnesium sulphate, filtered and then concentrated to dryness underreduced pressure (2.7 kPa) at 40° C. 76 g of a brown oil are thusobtained which are purified by chromatography on 3500 g of silica(0.04-0.063 mm) contained in a column with a diameter of 15 cm (eluent:dichloromethane). The fractions containing only the desired product arepooled and concentrated to dryness under reduced pressure (0.27 kPa) at400° C. 55.3 g of a mixture in a 65/35 molar ratio of the twodiastereo-isomers of 3-acetoxy-4-(4-cyanophenyl)-1-(S)-1-phenyl!ethyl-2-azetidinone are thus obtained in the form of anopalescent oil.

(S)-N-(4-Cyano)benzylidene(1-phenylethylamine) may be prepared in thefollowing manner:

To a solution of 25 g of 4-cyanobenzaldehyde in 200 cm³ ofdichloromethane, are added, with stirring and at a temperature close to20° C., 24.3 cm³ of (S)-1-phenylethylamine and 12 g of a 4 A molecularsieve. The reaction medium is stirred for 16 hours at a temperatureclose to 20° C. and then filtered on sintered glass containing celite.The sintered glass is washed with 3 times 50 cm³ of dichloromethane andthe filtrates are pooled and then concentrated to dryness under reducedpressure (2.7 kPa) at a temperature close to 40° C. 41.4 g of(S)-N-(4-cyano)benzylidene(1-phenylethylamine) are thus obtained in theform of a colourless oil.

EXAMPLE 10

To a solution of 2.2 g of methyl(2R,3S)-3-amino-3-(4-carbamoylphenyl)-2-hydroxypropionate in 50 cm³ oftetrahydrofuran, maintained under an argon atmosphere, are added at atemperature close to 20° C., 1.24 g of sodium hydrogen carbonate andthen 1.62 g of di-tert-butyl dicarbonate. The reaction medium is stirredfor 48 hours at a temperature close to 20° C. and then concentrated todryness under reduced pressure (2.7 kPa) at 40° C. and supplemented with20 cm³ of distilled water. The solid formed is separated by filtration,washed with 10 cm³ of distilled water and then 10 cm³ of diisopropylether and air dried. 2.1 g of methyl(2R,3S)-3-tert-butoxycarbonyl-amino-3-(4-carbamoylphenyl)-2-hydroxypropionateare thus obtained in the form of white crystals with a melting point of232° C. whose physical characteristics are as follows:

NMR spectrum: (300 MHz; DMSO-d₆ ; δ in ppm) 1.41 s, 9H: --NHCOOC(CH₃)₃!; 3.62 (s, 3H: --COOCH₃); 4.38 (d, J=4.5 Hz, 1H: --CHOH); 5.02 dd, J=10and 4.5 Hz, 1H: --CHNHCOOC(CH₃)₃ !; 5.65 (broad unresolved complex, 1H:--OH); 7.32 d, J=10 Hz, 1H: --NHCOOC(CH₃)₃ !; 7.39 and 8.00 (2s, 1Heach: --CONH₂); 7.41 d, J=8.5 Hz, 2H: --C6H₄ CONH₂ (--H2 and --H6)1;7.84 d, J=8.5 Hz, 2H: --C₆ H₄ CONH4(--H3 and --H5)!.

The product thus obtained is converted to 4-acatoxy-2α-banzoyloxy-5β,20-epoxy-1β, 7β, 10β-trihydroxy-9-oxo-11-taxen-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-(4-carbamoylphenyl)-propionate,the procedure being carried out under the conditions described inEuropean Patent EP 0,336,841.

EXAMPLE 11

To a mixture of 1.8 g of methyl(2R,3S)-3-tert-butoxycarbonylamino-3-(4-carbamoylphenyl)-2-hydroxypropionateand 15 cm³ of anhydrous pyridine, maintained under an argon atmosphere,are added, dropwise, at a temperature close to 20° C., 1.97 cm³ oftriethylchloromilane. When the addition is completed, the reactionmedium is stirred for 3 hours at a temperature close to 20° C. and thenpoured into a mixture of 200 cm³ of distilled water and 50 cm³ ofdichloromethane. The aqueous phase is separated by decantation and thenreextracted with 3 times 50 cm³ of dichloromethane. The organic phasesare pooled, dried over magnesium sulphate, filtered and thenconcentrated to dryness under reduced pressure (2.7 kPa) at 40° C. andthe crystals recovered are washed on sintered glass with 20 cm³ ofdiisopropyl ether. 1.92 g of methyl(2R,3S)-3-tert-butoxycarbonylamino-3-(4-carbamoylphenyl)-2-triethyl-silyloxypropionateare thus obtained in the form of white crystals with a melting point of165° C. whose physical characteristics are as follows:

NMR spectrum: (300 MHz; DMSO-d₆ ; δ in ppm). 0.43 (Mt, 6H: --OSi(CH₂CH₃)₃ ; 0.80 (t, J=7.5 Hz, 9H: --OSi(CH₂ CH₃)₃ ; 1.40 s, 9H--NHCOOC(CH₃)₃ !; 3.56 (s, 3H: --COOCH₃); 4.42 (d, J=4.5 Hz, 1H:--CHOH); 5.04 (dd, J=9.5 and 4.5 Hz, 1H: --CHNHCOOC(CH₃)₃,!; 7.33 d,J=9.5 Hz, 1H: --NHCOOC(CH₃)₃ !; 7.37 and 7.98 (2s, 1H each: --CONH₂);7.46 d, J=8.5 Hz, 2H: --C₆ H₄ CONH₂ (--H2 and --H6)!; 7.84 (d, J=8.5 Hz,2H: --C₆ H₄ CONH₂ (--H3 and --H5)!.

To a solution of 1.18 g of methyl(2R,3S)-3-tert-butoxycarbonylamino-3-(4-carbamoylphenyl)-2-triethylsilyloxypropionatein 20 cm³ of anhydrous pyridine, maintained under an argon atmosphere,is added, dropwise, at a temperature close to 0° C., 0.24 cm³ ofphosphorus oxychloride. When the addition is completed, the reactionmedium is stirred for 3 hours at a temperature close to 0° C. and thenpoured into a mixture of 100 cm³ of distilled water and 100 cm³ of asaturated aqueous solution of sodium hydrogen carbonate. After stirringfor 5 minutes at a temperature close to 20° C., 100 cm³ ofdichloromethane are added and then the aqueous phase is separated and itis reextracted with twice 80 cm³ of dichloromethane. The organic phasesare pooled, dried over magnesium sulphate, filtered and thenconcentrated to dryness under reduced pressure (2.7 kPa) at 40° C.

The residual solid is dissolved in 30 cm³ of methanol and supplementedwith 3 cm³ of a 1N aqueous solution of hydrochloric acid. The solutionobtained is stirred for 45 minutes at a temperature close to 20° C. andthen concentrated to dryness under reduced pressure (2.7 kPa) at 40° C.The residual solid is supplemented with 50 cm³ of a saturated aqueoussolution of sodium hydrogen carbonate and then extracted with 3 times 30cm³ of ethyl acetate. The organic phases are pooled, dried overmagnesium sulphate, filtered and then concentrated to dryness underreduced pressure (2.7 kPa) at 40° C. The crystals recovered are washedon sintered glass with 20 cm³ of diisopropyl ether. 0.75 g of methyl(2R,3S)-3-tert-butoxycarbonylamino-3-(4-cyanophenyl)-2-hydroxypropionateis thus obtained in the form of white crystals with a melting point of250° C. whose physical characteristics are as follows:

NMR spectrum: (200 MHz; DMSO-d₆ ; δ in ppm). 1.39 (s, 9H: --NHCOOC(CH₃)₃!; 3.62 (s, 3H: --COOCH₃); 4.39 (dd, J=8 and 4.5 Hz, 1H: --CHOH); 5.05dd, J=9.5 and 4.5 Hz, 1H: --CHNHCOOC(CH₃)₃ !; 5.65 (d, J=8 Hz, 1H:--OH); 7.40 d, J=9.5 Hz, 1H: --NHCOOC(CH₃)₃ !; 7.53 d, J=8.5 Hz, 2H:--C₆ H₄ CN(--H2 and --H6)!; 7.82 (d, J=8.5 Hz, 2H: --C₆ H₄ CN(--H3 and--H5)!.

The product thus obtained is converted to4-acetoxy-2α-benzoyloxy-5,β-epoxy-1β,7β,10β-trihydroxy-9-oxo-11-taxen-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-(4-cyanophenyl)-propionate,the procedure being carried out under the conditions described inEuropean Patent EP 0,336,841.

We claim:
 1. A method for preparing taxane derivatives comprising:(a)obtaining a compound of formula (I): ##STR18## by hydrogenolyzing acompound of the formula (II): ##STR19## wherein in formulae (I) and(II): Ar represents an aryl radical; R represents a hydrogen atom, analkyl radical containing 1 to 4 carbon atoms, or a phenyl radical,wherein the alkyl radical may be substituted by a phenyl radical; and Phrepresents a phenyl radical unsubstituted or substituted by at least oneatom or radical selected from halogen atoms, alkoxy radicals containing1 to 4 carbon atoms, alkylthio radicals containing 1 to 4 carbon atoms,amino radicals, alkylamino radicals containing 1 to 4 carbon atoms, anddialkylamino radicals in which each alkyl portion contains 1 to 4 carbonatoms; (b) converting the formula (I) compound to a compound of theformula (VIII): ##STR20## wherein: Ar is defined as above; R₃ representsa phenyl radical unsubstituted or substituted by at least one atom orradical, which are identical or different, selected from halogen atoms,alkyl, hydroxyl, alkoxy, alkanoyl, alkanoyloxy, nitro, amino,alkylamino, dialkylamino, carbamoyl, and trifluoromethyl radicals, thealkyl radicals and the alkyl portions of the other radicals containing 1to 4 carbon atoms, or R₃ represents a radical R₄ --O-- in which R₄represents:a straight or branched alkyl radical containing 1 to 8 carbonatoms, an alkenyl radical containing 3 to 6 carbon atoms, a cycloalkylradical containing 3 to 6 carbon atoms, a cycloalkenyl radicalcontaining 4 to 6 carbon atoms, these radicals unsubstituted orsubstituted by at least one substituent selected from halogen atoms,hydroxyl radicals, alkyloxy radicals containing 1 to 4 carbon atoms,dialkylamino radicals in which each alkyl portion contains 1 to 4 carbonatoms, piperidino radicals, morpholino radicals, 1-piperazinyl radicals(unsubstituted or substituted by an alkyl radical containing 1 to 4carbon atoms or by a phenylalkyl radical whose alkyl portion contains 1to 4 carbon atoms), cycloalkyl radicals containing 3 to 6 carbon atoms,alkenyl radicals containing 4 to 6 carbon atoms, phenyl radicals, cyanoradicals, carboxy radicals, and alkyloxycarbonyl radicals whose alkylportion contains 1 to 4 carbon atoms; a phenyl radical which isunsubstituted or substituted by at least one atom or radical selectedfrom halogen atoms, alkyl radicals containing 1 to 4 carbon atoms, andalkyloxy radicals containing 1 to 4 carbon atoms; or a saturated orunsaturated nitrogen-containing heterocyclic radical containing 4 to 6members and unsubstituted or substituted by at least one alkyl radicalcontaining 1 to 4 carbon atoms; and G₃ represents a group which protectsthe hydroxyl functional group;(c) reacting the formula (VIII) compoundwith a taxane derivative of the formula (IX): ##STR21## to obtain aproduct of formula X: ##STR22## wherein in formulae (IX) and (X), Ar,R₃, G₃ are defined as above, G₁ represents a group which protects thehydroxyl functional group, and G₂ represents an acetyl radical or agroup which protects the hydroxyl functional group; and (d) replacingthe groups G₁ and G₃ by hydrogen atoms, and replacing G₂ by a hydrogenatom when G₂ represents an hydroxyl-protecting group, to obtain a taxanecompound of the formula (VIl): ##STR23## in which Ar and R₃ are definedas above and R₂ represents a hydrogen atom or an acetyl radical.
 2. Themethod of claim 1, wherein Ar represents a phenyl or an α- or β-naphthylradical which is unsubstituted or substituted by at least one atom orradical selected from halogen atoms, alkyl, aryl, aralkyl, alkoxy,alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl,acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino,dialkylamino, carboxy, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl,cyano, nitro, and trifluoromethyl radicals, wherein the alkyl radicalsand the alkyl portions of the other radicals contain 1 to 4 carbon atomsand the aryl radicals are phenyl or α- or β-naphthyl radicals.
 3. Amethod for preparing taxane derivatives comprising:(a) converting aformula (I) compound: ##STR24## to a compound of the formula (VIII):##STR25## wherein: Ar represents an aryl radical; R represents ahydrogen atom, an alkyl radical containing 1 to 4 carbon atoms, or aphenyl radical, wherein the alkyl radical may be substituted by a phenylradical; and R₃ represents a phenyl radical unsubstituted or substitutedby at least one atom or radical, which are identical or different,selected from halogen atoms, alkyl, hydroxyl, alkoxy, alkanoyl,alkanoyloxy, nitro, amino, alkylamino, dialkylamino, carbamoyl, andtrifluoromethyl radicals, the alkyl radicals and the alkyl portions ofthe other radicals containing 1 to 4 carbon atoms, or R₃ represents aradical R₄ --O-- in which R₄ represents: a straight or branched alkylradical containing 1 to 8 carbon atoms, an alkenyl radical containing 3to 6 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms,a cycloalkenyl radical containing 4 to 6 carbon atoms, these radicalsunsubstituted or substituted by at least one substituent selected fromhalogen atoms, hydroxyl radicals, alkyloxy radicals containing 1 to 4carbon atoms, dialkylamino radicals in which each alkyl portion contains1 to 4 carbon atoms, piperidino radicals, morpholino radicals,1-piperazinyl radicals (unsubstituted or substituted by an alkyl radicalcontaining 1 to 4 carbon atoms or by a phenylalkyl radical whose alkylportion contains 1 to 4 carbon atoms), cycloalkyl radicals containing 3to 6 carbon atoms, alkenyl radicals containing 4 to 6 carbon atoms,phenyl radicals, cyano radicals, carboxy radicals, and alkyloxycarbonylradicals whose alkyl portion contains 1 to 4 carbon atoms; a phenylradical which is unsubstituted or substituted by at least one atom orradical selected from halogen atoms, alkyl radicals containing 1 to 4carbon atoms, and alkyloxy radicals containing 1 to 4 carbon atoms; or asaturated or unsaturated nitrogen-containing heterocyclic radicalcontaining 4 to 6 members and unsubstituted or substituted by at leastone alkyl radical containing 1 to 4 carbon atoms; and G₃ represents agroup which protects the hydroxyl functional group; (b) reacting theformula (VIII) compound with a taxane derivative of the formula (IX):##STR26## to obtain a product of formula X: ##STR27## wherein informulae (IX) and (X), Ar, R₃, G₃ are defined as above, G₁ represents agroup which protects the hydroxyl functional group, and G₂ represents anacetyl radical or a group which protects the hydroxyl functional group;and (c) replacing the groups G₁ and G₃ by hydrogen atoms, and replacingG₂ by a hydrogen atom when G₂ represents an hydroxyl-protecting group,to obtain a taxane compound of the formula (VII): ##STR28## in which Arand R₃ are defined as above and R₂ represents a hydrogen atom or anacetyl radical.
 4. The method according to claim 1 wherein G₁ isselected from 2,2,2-trichloroethoxycarbonyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, or triarylsilyl radicals in whicheach alkyl portion contains 1 to 4 carbon atoms and each aryl portionrepresents a phenyl radical.
 5. The method according to claim 1 whereinG₂ is selected from an acetyl or 2,2,2-trichloroethoxycarbonyl radical.6. The method according to claim 1 wherein G₃ is selected frommethoxymethyl, (1-ethoxy)ethyl, benzyloxymethyl,(β-trimethylsilylethoxy)methyl, tetrahydropyranyl,2,2,2-trichloroethoxymethyl, 2,2,2-trichloroethoxycarbonyl, anhydride,or mixed anhydride radicals, wherein the 2,2,2-trichloroethoxycarbonylradical is optionally substituted in the form of a halide.